P779: LONG-TERM COURSE OF HAX1-RELATED CONGENITAL NEUTROPENIA: AN ANALYSIS OF THE EUROPEAN SEVERE CHRONIC NEUTROPENIA INTERNATIONAL REGISTRY (SCNIR)
Authors: Denys Pogozhykh, Deniz Yilmaz Karapinar, Maksim Klimiankou, Natali Gerschmann, Georg Ebetsberger-Dachs, Jan Palmblad, Göran Carlsson, Tania Masmas, Sally Kinsey, Marije Bartels, Sabine Mellor-Heineke, Karl Welte, Julia Skokowa, Cornelia Zeidler
Journal: HemaSphere (2023)

Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background:HAX1-related congenital neutropenia (HAX1-CN; Kostmann syndrome), is an orphan autosomal recessive inborn disease caused by pathogenic mutations in the HAX1 gene. HAX1-CN contributes to 12.3% of genetically classified cases of CNs, being the third largest group after ELANE and SBDS associated neutropenias in the Severe Chronic Neutropenia International Registry (SCNIR) in Europe. Affected patients suffer from bone marrow failure, as assessed by a maturation arrest of the myelopoiesis, revealing persistent severe neutropenia in the peripheral blood (ANC less than 500/μl) from birth. The disorder is strongly associated with severe bacterial infections in untreated patients. Increase in ANC under G-CSF therapy has reduced infections significantly. Prolonged life expectancy has revealed a high risk for developing myelodysplastic syndrome or acute myeloid leukemia (MDS/AML). The SCNIR monitors the clinical course, treatment, and outcome of patients with severe chronic neutropenia subtypes since 1994, including the world’s largest collection of long-term data on HAX1-CN. Aims: The aim of this clinical observation study is to document the natural course of disease, response to treatment and long-term outcome of HAX1-CN patients. Methods: All HAX1-CN patients enrolled in the SCNIR in Europe were included in this report. Informed consents were obtained according to the Declaration of Helsinki. Standardized clinical parameters at diagnosis and during annual follow-up, as well as family history were collected by the registry. Results: Here we describe the course of HAX1-CN disease, response to treatment and long-term outcome in 72 patients with different types of HAX1 mutations enrolled in the SCNIR in Europe, which is the World’s largest cohort of pediatric and adult HAX1-CN patients reported. The patients cohort characteristics: 39 male, 33 female; 56 minor (below 18 years) and 16 adults (median age 10.4 years, range 1 to 40.8 years). All 72 patients received long-term treatment with hematopoietic growth factor G-CSF and responded well to individual G-CSF doses, (median dose 3.59 µg/kg/d). All studied patients benefit from G-CSF therapy, which results in significant reduction of infections and overall improvement of quality of life. MDS/AML has developed in 11% of the studied cohort in all ages. Acquired somatic mutations in CSF3R and other leukemia-associated genes play a role in leukemogenesis and may be detected prior to MDS/AML. Non-hematological manifestations frequently include CNS (seizures), musculoskeletal system (short statue), and reproductive system (various hypogonadism forms). Summary/Conclusion: Patients with all known types of HAX1 mutations present with severe congenital neutropenia, but respond well to long-term G-CSF treatment. Continuous G-CSF therapy significantly improves the quality of life and allows pediatric patients to reach adulthood. Secondary ovarian insufficiency is frequently observed in young HAX1-CN female patients early after puberty and should be closely monitored during the course of disease. Patients with MDS/AML require stem cell transplantation. Regular monitoring of somatic leukemia associated mutations is recommended. The SCNIR provides a long-term follow up and monitoring of severe neutropenic patients, including the collection of the CN patient´s samples in a centralized biobank, which enables bringing forward the understanding of the mechanisms and consequences of this orphan disease, as well as development of efficient diagnostic and treatment standards. Keywords: Neutropenia, Myelodysplastic syndrome, Bone marrow failure, Acute myeloid leukemia